Metal containing molecules were studied in the gas phase. These compounds were synthesized in a Broida-type oven by the high temperature reaction between metal atoms and appropriate oxidants. The laser-induced fluorescence technique was employed to detect the products from these reactions. These inorganic molecules, consisting of a metal atom bonded to a single ligand, are ionic and can be represented by the structure M⁺L⁻(M = Ca, Sr, Ba and Cu). The BaOH and BaOD molecules were studied at low resolution. The band origins were found and the vibrational assignments were carried out for the Ã²Π-X²Σ⁺ transition, which has been previously seen. The nominally forbidden Ã' ²Δ-X² Σ⁺ transition was observed for the first time for alkaline earth polyatomics. Three electronic transitions were detected for the metal monohydrosulphides and metal monothiolates. The spectra are consistent with a bent Ca-S-R structure. Some Ca-S and Sr-S stretching frequencies were determined from the spectra. The B¹A"-X¹A' transition of CuOD molecule was rotationally analyzed at high resolution using the filtered laser excitation technique. Rotational lines up to K', K" = 7 sub bands have been measured. Molecular constants were obtained for the ground and excited states by fitting these lines to a asymmetric rotor Hamiltonian. These constants will be helpful for assigning the red systems of CuOH and CuOD. The emission spectra of boron containing compounds, BC, BH and BD, were recorded using a high resolution Fourier transform spectrometer. These compounds were made in a B₄C/Cu composite-wall hollow cathode lamp. The B⁴Σ⁻-X⁴Σ⁻ transition of BC was observed near 17900 cm⁻¹. The ground state internuclear separation was found to be 1.488A. The rotational constants for different vibrational levels were obtained from fitting the rotational lines. The A¹Π-X¹Σ transition was analyzed for BH and BD in order to find accurate rotational line positions and precise molecular constants. The rotational lines of BH were fit to a Dunham-type expression and equilibrium molecular constants were obtained. The vibrational levels of the A¹Π state are very anharmonic. During the course of the study of BD, the A¹Σ⁺-X¹Σ⁺ transition of CuD was also observed. This spectrum contained rotational lines from both ⁶³CuD and ⁶⁵CuD isotopomers and improved molecular constants were obtained by the analysis of the data.

Some space-constraining amino acid-containing oxytocin analogues were synthesized, of which the biological activities were found to be remarkably consistent with the predictions based on molecular mechanics calculations using the CHARMM program. Correlations of the biological activities and computer modeling studies of the conformational properties of Tyr², Phe², eBmp² (agonists), Pen¹, and Tic² (antagonists) oxytocin analogs revealed that a g+ conformation for the aromatic ring in the 2-position is important for the oxytocin-uterus receptor transduction. Examination of the topographical features of the energy minimized conformations of these analogs shows that a parallel aromatic surface over the top of the 20-membered disulfide containing ring of the molecule is equally important for the transduction. Though the Tic compound may exclusively exist as the g+ conformation for the aromatic ring in the 2-position, possible backbone changes and particularly the perpendicularly located aromatic ring on the top of the 20-membered ring may be the reason for its antagonism. Calculations shows that (erythro(2S, 3S)-β-methyltyrosine²) OXT has all the requirements for being an highly active compound, while the isomer (threo-L-(2S, 3R)-β-methyltyrosine²) OXT, which differs only in the configuration of the β carbon, is unlikely to be an agonist according to our calculations. Both compounds were synthesized together with other analogs by the solid-phase peptide synthesis techniques on p-methyl-benzhydrylamine resin. The biological activities of these two compounds were consistent with the predictions.

The aim of this work was to study the solution conformation of dimeric and polymeric 1actams. In a first part of this work, the synthesis of bicyc1odi1actams as precursors of the polymers was explored. A new preparation for the 2, 5-diazabicyc1o [2,2,2] octa-3, 6-dione was developed. The dimers and polymers were obtained from the N-protected cis- and trans- 3-amino-6-carboxy-2-piperidone for which an improved synthesis was found. Base treatment of the trans activated ester led to the polymer. Using the methods of solution phase peptide synthesis, the four possible dimers were prepared. After transformation to the paranitrophenyl esters, they polymerized to oligomeric species under the same treatment. The solution conformation of the monomeric, dimeric and polymeric species was determined by 1- and 2-dimensional NMR techniques. The 1actam rings have a chair-like conformation in solution. The cis- 1actam is a powerful β-turn- inducer when incorporated in synthetic peptides. The cis- lactam was found, however, to have a very similar conformation in DMSO solution, without hydrogen bonding to stabilize the turn. No evidence was found for the β-turn in the dimers and polymers using 2-dimensional NMR techniques. The dimers were found to exist in an extended conformation in DMSO. The fact that every other amide bond is in the cis configuration, as well as the steric crowding due to the rings may not allow the existence of the β-turn.

Very early in the history of atomic emission spectroscopy (AES) it was understood to be a powerful analytical tool. Until the 1930's the usefulness of atomic spectroscopy was not utilized very extensively even though its fundamental power was understood. The breakthrough that placed it in the standard chemistry laboratory was the discovery and implementation of the photoelectric effect. Since this discovery there has been a revolution in atomic spectroscopy which has brought it from the role of a humble servant used for primary elemental screening to an outstanding leader in applications of elemental analysis. Atomic emission spectroscopy of complex samples has long suffered from matrix effects which result in overlapping of spectral lines, fluctuating backgrounds and changing conditions in the source. Investigations employing an echelle polychromator with a two dimensional solid state array detector show great promise in minimizing the effects of these interferences on multielement analyses of complex samples. The Charge Injection Device (CID) detector used exhibits many characteristics which make it uniquely qualified for simultaneous, multielement detection in AES. With only slight modifications to the optics of a commercial spectrometer and the employment of a CID detector, detection limits for a number of elements are quite favorable. Dynamic ranges of over seven orders of magnitude are obtainable with this experimental system. The reduction of matrix effects by utilizing the huge wealth of information available from over 60,000 individual detector elements are demonstrated through results from several complex matrix standards. This CID-polychromator system was also employed for the element selective detection of gas chromatographic (GC) effluents. A microwave-induced plasma (MIP) based on the Surfatron design was built. A helium plasma from this device has shown to have resilience to organic samples and give good emission response to non-metallic atoms. A number of studies with this GC-AES-polychromator system are presented. This system is capable of monitoring atomic emissions from C, H, F, Cl, Br, I, O, N and S all simultaneously, and the selectivity of this system is unsurpassed. Elemental ratios for separated compounds are also presented as a precursor to empirical formula prediction.

The reversible phosphorylation of proteins plays a key role in nearly every aspect of cell life. This essential post-translational modification controls a myriad of cellular events from cell survival, differentiation, and migration to apoptosis. Two classes of enzymes, kinases and phosphatases, tightly control all phosphorylation events. Perturbation in the activity of any member of these classes of enzymes has been linked to numerous diseases including cancer, metabolic disorders, immune disorders and neurological disorders. Therefore, there is a great interest among the scientific community to develop methods to selectively modulate the activity of kinases and phosphatases not only for therapeutic purposes but also to understand the fundamental role of these enzymes in signaling events. The more than 500 kinases encoded in the human genome share a common catalytic fold and most inhibitors target the ATP binding site. Therefore selective targeting of a single kinase by an inhibitor at the highly conserved ATP binding site is one of the main concerns for designing probes or drugs. Our group has taken advantage of the potency and possible selectivity imparted by bivalent inhibitors and developed an in vitro selection approach to discover bivalent ligands. The strategy involves the use of an ATP-competitive small molecule warhead and a library of cyclic peptides displayed on phage that interact with the kinase of interest in a dynamic selection. The selection for a kinase binding peptide is carried out until consensus peptides are found and bivalent ligands are constructed by linking the selected cyclic peptide with the small molecule warhead through a synthetic linker. Using this approach a potent and selective bivalent inhibitor was found for PKA, a serine/threonine kinase. To interrogate the generality of this approach, a kinase closely related to PKA (PRKX) was used for which a very potent and selective bivalent ligand was found. The same selection strategy was further extended to the two kinases Lyn and Brk, which belong to the tyrosine kinase family. Though peptides were isolated that bound the desired kinase, potent bivalent inhibitors were not discovered. More generally, these experiments in sum are building a library of information regarding how to best design selections of potent and selective bivalent inhibitors. We further explored modulation of the activity of kinases and phosphatases by employing a ligand-gated split-protein approach. The small molecule gated spatial and temporal control of these enzymes should allow the study of signaling events in a controlled manner. The strategy employed consists in the identification of possible fragmentation sites within the catalytic domain of kinases and phosphatases by a sequence dissimilarity approach. Loop insertion mutants at the selected sites were tested for catalytic activity. Successful insertion mutants were further split into two catalytically inactive fragments, which were appended to two conditionally interacting protein domains. Upon addition of a small molecule, the two conditionally interacting domains reassemble the catalytic domain of the enzyme and restore catalytic activity. Using this approach we were able to modulate the activity of the tyrosine kinases Lyn, Fak and Src and the AGC kinase PKA. We also extended the approach to gate the activity of tyrosine phosphatases PTP1B, SHP1 and PTPH1. Finally, these ligand-gated split-kinases and phosphatases were validated in-cellulo. Thus, this work resulted in a new method for designing split-proteins and provided a palette of kinases and phosphatases that can be turned-on by small molecules. In total, these efforts describe two alternative routes that can be used to modulate phosphorylation events in a selective and controlled manner.

The first systematic study of the effect of variations in initiator and monomer concentrations on two-dimensional polymerizations is described here. The number average degree of polymerization, X(n), was estimated by SEC for the thermal polymerization of bilayers composed of a mono-substituted acryloyl phospholipid. When the monomer to initiator (azobisiso-butyronitrile) molar ratio, [M]/[I], was varied from 5 to 40, holding [M] constant, the X(n) increased from 233 to 1,936. The measured X(n) was observed to be inversely proportional to the initiator concentration. When the monomer concentration was diluted by the incorporation of a nonpolymerizable lipid (DMPC), the X(n) was decreased from 1,476 for pure mono-acryloyl PC to 299 for a 1/1 molar ratio of mono-acryloyl PC and DMPC. The X(n) was found to be dependent on the square of the monomer mole fraction in the bilayers. The polymerization of bis-acryloyl PC produced much shorter polymers than mono-acryloyl PC but appeared to have the same dependency on initiator concentration. These data suggest that this two-dimensional polymerization is preferentially terminated by reaction with initiator fragments rather than by the usual radical coupling and/or disproportionation reactions of the growing polymer chains. It is suggested that the preference for termination by small molecular fragments is a consequence of limited diffusion of the growing polymer chains in the constrained environment of the lipid bilayer. Furthermore these data demonstrate that careful attention to the ratio of [M]/[I] is necessary to reproducibly control the size and properties of polymers formed in supramolecular assemblies.

Immunological reagents were prepared and characterized for the development of analytical methodology in bioanalytical research. Monoclonal antibodies to glucose oxidase (E.C. 1.1.3.4) from Aspergillus niger were prepared with apoenzyme as the antigen. Five of these antibodies, all of the IgG, subisotype, were further characterized. The carbohydrate moiety of the enzyme is not immunogenic. Binding of the five antibodies to the enzyme had no detectable effect on its catalytic properties. All the antibodies are shown to be directed towards segmental epitopes of the enzyme, not involving the carbohydrate moiety. Each enzyme subunit has more than one non-overlapping epitope. All five antibodies bound enzyme in a non-native conformation when coated on ELISA plates in preference to the native solution conformation. The importance of having a solution phase screening procedure for monoclonal antibodies is demonstrated. Factors affecting the specific activity of immobilized antibodies and their biologically active fragments were studied with goat anti-mouse and goat anti-human IgG. Antibodies were immobilized on HW 65 polymeric support matrix activated with carbonyldiimidazole, hydrazide and iodoacetic acid. The most significant factors influencing the specific activity of stochastic coupling of antibodies are multisite attachment, multiple orientations, and steric hindrance imposed by crowding of antibody and the size of the antigen. With oriented immobilization the specific activity is affected only by steric hindrance. The specific activity of immunosorbents prepared by immobilization of F(ab') fragments can be improved to almost 100% by limiting the amount of protein immobilization and the size of the antigen. The present study shows the protocols for optimizing immobilized antibody performance. Preparation of fragments of immunoglobulin were studied. Within the same species different antibodies showed different sensitivities to proteolytic cleavage by pepsin. A rapid, simple, high performance size exclusion chromatographic method was developed to monitor the reaction progress. Conditions must be optimized for each antibody in the preparation of F(ab')₂. Preparation of F(ab') from F(ab')₂ shows that 10-15% of goat anti-mouse F(ab')₂ was resistant to reduction. The procedure causes reduction of disulfide bonds other than the inter-heavy chain disulfide bonds.

Operational characteristics and performance of two mass spectrometers incorporating improved versions of the Very High Yield Electron Impact (VHY-EI) ion source are described. The ionizers are designed around a large volume, low pressure, hot cathode Penning geometry and operate at source pressures of 10⁻⁵ torr and below. In combination with low spherical aberration focusing optics, mass analyzed ion currents 100 to 1000 times more intense than those produced by conventional ionizers operated under identical or comparable conditions of resolution, analyzer type, sample pressure, and electron impact energy are obtained. In addition, high ionization-mass analysis efficiencies have been demonstrated for a variety of organic compounds with sample mass flow rates approaching 1 mg/min. Typical electron impact spectra are obtained with no evidence of pyrolysis or ion molecule reactions. Unusually intense spectra can be produced with low energy electrons.

There are two main objectives for this thesis. First, laboratory rotational spectra of metal-containing molecules were measured using the millimeter-wave spectrometers of the Ziurys group. Second, radio astronomical observations were performed on a number of the molecules measured in the laboratory, along with several organic species. The laboratory work is essential to the discovery of new molecules in the interstellar medium, and the understanding of the chemical composition of the universe. Identification of these species can only occur after their pure rotational spectra have been measured. Therefore, an investigation of the rotational spectra of several classes of molecules was performed including metal-bearing hydrides, chlorides, carbon-containing species, and molecular ions. The experimental measurements were aided by necessary improvements in the operation of the spectrometers. Many of these species had not been observed by any spectroscopic technique, including CaC, CuCH₃, FeCO⁺ and VCl⁺. Several of these molecules exhibited unusual interactions that complicated the analysis of their spectra, such as VCl, TiCl⁺, VCl⁺, and FeCO⁺. Synthesis of these species required exotic production techniques, including the use of Broida ovens and AC and DC discharges. Astronomical observations of several of the molecules studied in the laboratory were conducted, and upper limits to the abundances obtained. Additional searches for more of the species studied are planned. A region in the Galactic center with a complex chemical composition called Sgr B2(N) was recognized through observations of N₂O. Several organic species were then searched for in this source. The detection of the simple sugar glycolaldehyde was confirmed by observing all of the favorable transitions of this molecule in Sgr B2(N). A standard set of criteria for identifying complex organic molecules was drawn up as a result of this study. This investigation led to an attempt to confirm a larger sugar, dihydroxyacetone. Unfortunately the detection of this species was proven false, and a limit could be placed on the chemical complexity of this source.

This research utilized a structural analysis of final judgment and a process-tracing method to examine the effects of situational involvement and task complexity on information acquisition and the decision-making process. In addition, the predictive accuracy of the linear model in predicting drug choice across decision situations was assessed. A contingency model for the selection of decision strategies based on a cost/benefit principle was used as a framework in the study. A randomized mixed model factorial design was conducted in which a sample of forty-eight physicians, recruited from the University Medical Center at the University of Arizona, indicated their preferences and choices for hypothetical anti-infective drugs. Subjects were randomly assigned to experimental and control groups. Subjects in the experimental group were told via the written scenario to assume that his/her decision would be reviewed and evaluated by peers and (s)he would be asked to justify drug choice. No mention of peer review was made in the scenario used by the control group. Subjects in both groups were required to perform the two choice tasks and conjoint ranking task. The number of drug alternatives in a choice set was varied between three and six alternatives. The Mouselab program was used to monitor physicians' information acquisition behavior. The measures concerning the amount of information searched, order, duration, direction of search, and the chosen alternative were observed. The conjoint LINMAP program was used to estimate drug attribute importance weights. Results of the study provide support that the information acquisition and decision-making process is contingent on the characteristics of decision tasks. A significant number of subjects shifted from using compensatory to noncompensatory decision-making processes when task complexity increased. The study did not find support for the effects of situational involvement on the decision-making process. However, subjects in the two groups were found to differ in choice outcomes and the attention given to specific drug attribute information. Finally, the study found support for the robustness of the linear models in predicting drug choice across contexts.

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